2-halo-1,1,1,3,3-pentafluoropropanes

ABSTRACT

2-CHLORO-1,1,1,3,3-PENTAFLUOROPROPANE AND 2-BROMO-1,1, 1,3,3-PENTAFLUOROPROPANE, USEFUL AS NONFLAMMABLE INHALATION ANESTHETICS, AND THE INTERMEDIATE 1,1,1,3,3-PENTAFLUOROPROPAN-2-OL AND P-TOLUENESULFONATE ESTER OF SAID ALCOHOL USED IN PREPARING THE INHALATION ANESTHETICS.

United States Patent 3,585,245 2-HALO-1,1,1,3,3-PENTAFLUOROPROPANES Bernard M. Regan, Chicago, Ill., assignor to Baxter Laboratories, Inc., Morton Grove, Ill.

No Drawing. Original application Aug. 29, 1967, Ser. No. 663,952, now Patent No. 3,499,089, dated Mar. 3, 1970. Divided and this application July 7, 1969, Ser. No. 862,550 The portion of the term of the patent subsequent to Jan. 9, 1985, has been disclaimed Int. Cl. C07c 19/08 US. Cl. 260-653 3 Claims ABSTRACT OF THE DISCLOSURE 2-chloro-1,l,1,3,3-pentafluoropropane and 2-bromo-1,1, 1,3,3-pentafluoropropane, useful as nonflammable inhalation anesthetics, and the intermediate 1,1,1,3,3-pentafluoropropan-Z-ol and p-toluenesulfonate ester of said alcohol used in preparing the inhalation anesthetics.

This application is a division of application Ser. No. 663,952, filed Aug. 29, 1967, now Pat. No. 3,499,089, granted Mar. 3, 1970.

This invention relates to novel halopentafiuoropropanes. More particularly, this invention relates to certain monohalopentafluoropropanes having a chlorine or bromine atom substituted on the number two carbon atom, namely, 2 chloro 1,1,1,3,3 pentafluoropropane and 2- bromo-l, 1,1,3 ,3-pentafluoropropane.

It is known that certain halogenated alkanes are useful inhalation anesthetics. Chloroform and halothane are well-known examples of such compounds which are derivatives of the lower alkanes, methane and ethane, respectively. More recently, it has also been disclosed that certain halogenated propanes are useful inhalation ane's'thetics. Thus, Dishart, US. Pat. 3,034,959, discloses the inhalation anesthetic use of 2-bromo-1,1,2,2-tetrafluoropropane and Belgian Pats. 663,478 and 668,605 disclose the inhalation anesthetic use of 3bromo-3-chloro-1,1,1, 2,2-pentafluoropropane.

Position isomers of the monohalopentafluoropropanes of the present invention also are known. Thus, 3-bromoand 3-chloro-l,1,1,2,2-pentafluoropropanes are disclosed by McBee et al., 77 J. Am. Chem. Socy. 3149 (1955); 3-bromo 1,1,1,3,3 pentafiuoropropane is disclosed by fluoropropane is disclosed by Henne et al., 68 J. Am. Chem. Socy. 446 (1946) and Arnold, US. Pat. 2,558,- Muray, British Pat. 908,110; 3-chloro-1,1,1,3,3-penta- 703; 3-bromoand 3-chloro-1,l,2,2,3-pentafiuoropropanes and l-bromoand l-chloro-1,1,2,2,3-pentafluoropropanes are disclosed in a dissertation by Beck, Reactives of Aliphatic Fluorides, The Ohio State University (1959); and 2-bromo-l,1,l,2,3-pentafluoropropane is disclosed by Rausch et al.; 28 J. Org. Chem. 494 (1963).

Three er the above position isomers of the monohalopentafiuoropropanes of the present invention have been further disclosed as having inhalation anesthetic properties. Thus, Raventos, British Pat. 913,143, discloses the inhalation anesthetic properties of 3 -bromol,l,1,3,3- pentafluoropropane and Burns et al., 17 Anaesthesia 337- 43 1962), disclose the inhalation anesthetic properties of the 3-bromoand 3-chloro-1,l,1,2,2-pentafiuoropropanes.

It has now been found that the novel monohalopentafluoropropanes having a chlorine or a bromine atom substituted on the number two carbon atom, as defined herein, are useful inhalation anesthetics which have inhalation margins of safety in mice which are substantially higher than the margins of safety of the inhalation anesthetics in current use, namely, ether, chloroform, and

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halothane. Moreover, these margins of safety of the novel monohalopentafiuoropropanes of this invention are also substantially higher than the margins of safety of the above-mentioned position isomers disclosed by Raventos and Burns et al. As such, the compounds of this invention hold good promise as effective and useful agents for inducing anesthesia in man.

The novel inhalation anesthetic compounds of this invention also have been found to be nonflammable in air at ambient temperatures and nonexplosive in oxygen. The flammability margins of safety of these compounds in oxygen are substantially higher than the margins of safety of the above-mentioned position isomers of these compounds which are disclosed by Burns et a1. as having inhalation anesthetic properties.

The anesthetic compounds of the present invention can be administered by apparatus or machines designed for the vaporization of liquid anesthetics and admixtures thereof with oxygen, air or other gaseous mixtures containing oxygen in amounts capable of supporting respiration.

The novel 2-chloro-1,1,1,3,3-pentafluoropropane boils at 39 C. and the novel 2-bromo-1,1,1,3,3-pentafluoropropane boils at 57.5 C. Each of these compounds can be conveniently stored in containers normally used for conventional inhalation anesthetics of comparable boiling points, e.g., ether, chloroform and halothane.

For use in anesthesia, the compounds of the present invention should be free from toxic impurities which may be present according to the particular process used for their manufacture. These compounds can, however, be used in admixture with pharmaceutically acceptable substances such as stabilizers, e.g., thymol, or one or more of the known inhalation anesthetics, e.g., nitrous oxide, ether, halothane, chloroform, cyclopropane, methoxyfluorane and the like.

The novel monohalopentafluoropropanes defined herein can be conveniently prepared from a suitable alkali metal halide and the p-toluenesulfonate ester of 1,1,1,3,3-pentafluoropropan-Z-ol by reaction at about 210 C. to about 230 C. in a suitable diluent followed by separation of the desired products from the reaction mixture.

Potassium bromide is the preferred alkali metal halide used for the preparation of 2-bromo-1,1,1,2,3-pentafluoropropane and lithium chloride is the preferred alkali metal halide used for the preparation of 2-chloro-1,1,1,3,3-pentafluoropropane. Other alkali metal halides can be substituted for the above potassium bromide and lithium chloride provided that they are sufficiently soluble in the diluent to provide suitable reaction. Generally, from about one to about two moles of the alkali metal halide are used per mole of p-toluenesulfonate ester in the above reaction.

Examples of suitable diluents for use in the above reaction are: sulfones such as diethyl sulfone, dimethyl sulfone and tetramethylene sulfone.

Although a reaction temperature of from about 210 C. to about 230 C. is described above, it will be understood that there can be some variation in this temperature, depending upon the boiling point of the diluent and other conditions of the reaction.

Upon completion of the above reaction, the desired products can be separated from the other reaction products by fractional distillation with or without prior washings with water. An oxidant, for example, hydrogen peroxide or potassium permanganate, can be employed prior to distillation of the desired products to remove undesirable impurities, such as sulfides derived from the sulfone solvents used in the preparation of the monohalopentafluoropropanes of this invention.

The intermediate p-toluenesulfonate ester of 1,1,1,3,3- pentafluoropropan-Z-ol which is used to prepare the novel inhalation anesthetics defined herein also is a novel compound. It can be conveniently prepared by reacting a mixture of 1,1,1,3,3-pentafiuoropropan-2-ol and an equimolar equivalent of p-toluenesulfonyl chloride with a slight molar excess of sodium hydroxide or similar such alkali in water, preferably at about 20 C. to about 40 C., and then separating the 1,1,1,3,3-pentafluoro-2-propyl p-toluenesulfonate from the other reaction products.

The intermediate 1,l,1,3,3 pentafluoropropan 2 01 which is used to prepare the novel inhalation anesthetics defined herein also is a novel compound. It can be conveniently prepared by reduction of chloropentafiuoroacetone with about five molar equivalents of hydrogen and a catalyst of palladium on carbon, preferably in the vapor phase at about 180 C., and then separating the desired 1,1,1,3,3-pentafluoropropan-2-ol from the other reaction products by fractional distillation.

The novel 1,1,1,3,3-pentafluoropropan-2-ol defined herein also is useful as a solvent, particularly for compounds that contain receptive sites for the strong hydrogen-bonding donor properties of this alcohol. Among these compounds are polymers such as polyformaldehyde, nylon and other polyamides, polyacrylonitrile, polyvinyl alcohol, and polyesters. The novel alcohol also is a solvent for natural products containing amide, amino, ester, alcohol or ketone groups.

Although the above methods of preparation and reaction conditions are specifically described, it will be understood that the novel compounds of this invention are not limited to these specific reaction conditions or to these specific methods of preparation.

The following examples will further illustrate the present invention, although the invention is not limited to these specific examples. All percentages and parts herein are on a weight basis unless otherwise specified.

EXAMPLE I 1,1,1,3,3-pentafluoropropan-2-ol (I): Hydrogen at the rate of one liter per minute and the vapor of chloropentafluoroacetone at the rate of 1.5 grams per minute were mixed and passed through a Pyrex tube (45 cm. x 1.9 cm. I.D.) containing 2% palladium on carbon granules (4-12 mesh) and heated to 180 C. The reaction products were condensed in a trap cooled by Dry Ice.

[In a typical run 480 grams (2.63 moles) of chloropentafluoroacetone was vaporized with hydrogen during 5.5 hours, and the mixture passed over 85 grams of palladiumcarbon catalyst. Fractional distillation of the 358 grams of reaction products gave 258 grams, 1.72 moles, 65% of theory) of crude alcohol (I), B.P. 81 C. Its infrared spectrum is consistent with the CF CH(OH)CHF structure.

Analysis.-Calcd for C H F O (percent): C, 24.01; H, 2.04. Found (percent): C, 23.99; H, 2.18.

EXAMPLE II 1,1,1,3,3-pentafluoro-2-propyl p-toluenesulfonate (II) A mixture of crude 1,1,l,3,3-pentafluoropropan-2-ol (I) (750 grams, 5.00 moles), p-toluenesulfonylchloride (954 grams, 5.00 moles) and 1200 ml. of water was stirred as 5 N sodium hydroxide solution (1050 ml., 5.25 moles) was added during about 3 hours, and the temperature was maintained between 25 40 C. Stirring was continued for about 16 hours. The crude ester (II) was separated, stirred, evacuated to between 25-40 mm. Hg and heated to 125 C. until volatile impurities ceased to distill. About 1445 grams (4.75 moles, 95% of theory) of crude tosyl ester (H) was obtained. Crystallization from petroleum ether gave purified tosyl ester (II), M.P. 26 C.

AnaIysis.Calcd for C H F O S (percent): C, 39.48; H, 2.98; F, 31.22; S, 10.54. Found (percent): C, 39.50; H, 3.21; F, 32.67; S, 11.51.

4 EXAMPLE III 2-bromo-1,l,1,3,3-pentafluoropropane (III): To a stirred mixture of potassium bromide (450 grams, 3.78 moles) in 1250 grams of dimethyl sulfone heated to 225 C., crude 1,1,1,3,3-penta1fluoro-2-propyl p-toluenesulfonate (II) (770 grams, 2.53 moles) was added. As III formed, it distilled through a Vigreaux column and descended through a cold-water spiral condensor. The product was collected in an ice-cooled receiver and washed with water to yield 310 grams (1.46 moles, 58% of theory) of crude III having an unpleasant sulfide-like odor. It was treated with 50 ml. of acidified 10% potassium permanganate solution with stirring at room temperature overnight. The bromide III was separated, washed with water, dried by azeotropic distillation and fractionally distilled to give about 242 grams (1.14 moles, 45% of theory) of III, b 56.657.0 C. d, 1.8637 and n 1.3332. It was found to be 99.6% pure by gasliquid partition chromatography. Its 60 mc. nuclear magnetic resonance and infrared spectra confirm the CF CHBr-CI-IF structure.

EXAMPIJE IV 2 chloro-1,1,1,3,3-pentafluoropropane (IV): To a stirred mixture of potassium chloride (200' grams, 2.69 moles) and 865 grams of dimethylsulfone heated to 225 C., crude 1,1,1,3,3-pentafluoro-2-propyl p-toluene sulfonate (530 grams, 1.73 moles) was added. Very little product distilled during 2 hours, so the reaction mixture was cooled and anhydrous lithium chloride (42.4 grams, 1.00 mole) was added. Upon heating the reaction mixture to 225 0., product began distilling at a reasonable rate. Altogether 157 grams (0.93 mole, 54% of theory) of crude IV was collected. It was washed with water and stirred with 50 ml. of acidified 10% potassium permanganate solution overnight at room temperature. The chlo ride IV was separated, Washed with water, dried by azeotropic distillation and fractionally distilled to give 118.5 grams (0.70 mole, 41% of theory) of IV, b 38.2-38.6 C. A fraction of this assaying 99.7% by gas-liquid partition chromatography has d 1.5059 and n 1.3010. Its nuclear magnetic resonance and infrared spectra confirm the CF CHClCHF structure.

EXAMPLE V Inhalation of the vapor of 2-bromo-1,1,1,3,3-pentafiuoropropane or 2-chloro 1,1,1,3,3 pentafluoropropane admixed with air according to the procedure described by Robbins, 86 J. Pharmacol. Exper. Therap., 197-204 (1946), produced anesthesia in white mice. The minimum concentration by volume percent needed to produce full anesthesia in 50% of the mice in five minutes, AC and the minimum concentration by volume percent needed to kill 50% of the mice in five minutes, LC are given in Table 1, below. The inhalation margin of safety as calculated for mice by the LC /AC ratio is also given for the above compounds. For purposes of comparison, similar data which were obtained under the same conditions as for the above compounds are given for three inhalation anesthetics in current use, viz., ether, chloroform, and halothane, and for the 3-bromo-pentafluoropropanes which are position isomers of the inhalation anesthetic compounds of this invention and disclosed by Raventos and Burns et al. as having inhalation anesthetic properties. The number of mice used with the different agents varied from 25 to 92 for determining each of the AC50 and LC50 doses.

TABLE 1-INHALA1ION AN'ES'IEIESIA. IN MICE The results set forth in the above table show a sub stantial and significant improvement in the inhalation margin of safety of the inhalation anesthetic compounds of this invention compared to the three inhalation anesthetics in current use and to the isomeric 3-bromo-pentafiuoropropanes.

EXAMPLE YI Four dogs were anesthetized with 2-bromo-l,l,l,3,3- pentafluoropropane at concentrations ranging from 0.5 to 1.5 volume percent in admixture with oxygen. For purposes of comparison, five dogs were anesthetized under the same conditions with halothane at concentrations ranging from 1 to 2 volume percent in admixture with oxygen. The higher concentrations of the anesthetics were the amounts required to induce full anesthesia and the lower concentrations were the amounts required to maintain surgical anesthesia (stage III, plane 2) in the animals.

The anesthetic mixture was administered via an endotracheal catheter with inflation cuffs in a non-rebreathing system subsequent to initial anesthesia with sodium methohexital and pretreatment with atropine sulfate and heparin.

Heart rate and myocardial responses were determined from EKG records. Spontaneous respiratory rate and respiratory minute volume were monitored by means of a pressure change transducer and a wet-test meter, respectively. The arterial blood pressure was monitored, and blood samples were Withdrawn for determinations of blood gases and pH.

Anethesia with 2 bromo-l,1,1,3,3-pentafluoropropane was substantially equivalent to anesthesia with halothane. Both compounds produced a fall in diastolic blood pressure below 70 mm. Hg in three dogs and a decrease in heart rate. Normal respiratory minute volume and normal pCO values were observed for both compounds in four out of four dogs. The EKG records were normal for both compounds, with the exception that T-wave inversion occurred in three out of four dogs with 2-bromo- 1,l,l,3,3-pentafluoropropane and in four out of five dogs with halothane.

EXAMPLE VII The flammability of gaseous mixtures of the novel inhalation anesthetics of the present invention and air or oxygen was determined at room temperature and atmospheric pressure by visualization of the downward propagation of a flame in a glass bottle having a cylindrical portion 2.3 inches LD. x 3.5 inches in height. The bottle was flushed with pure oxygen or air, a known quantity of liquid anesthetic added rapidly, and the bottle closed with a ground glass stopper. The bottle was then rotated and shaken until the liquid anesthetic was completely vaporized and uniformly mixed with oxygen or air. The stopper was then removed and immediately a burning stick inserted in the bottle 1.5 to 2.0 inches below the bottle mouth.

The concentration by volume percent of the gaseous anesthetic in oxygen or air was calculated by well-known computation means employing the known volume of the stoppered bottle (i.e., the volume of the contained oxygen or air), the known volume of the added liquid anesthetic, the known densities and molecular weights and application of the ideal gas law to compute the gaseous volume of the anesthetic sample.

The lower flammability limits in oxygen, LFlO and in air, LFlAir, as determined by the above procedure are given in Table 2, below. These flammability limits are stated as a range of two concentrations by volume percent of the anesthetic in the gaseous mixture; downward flame propagation was observed at the higher concentration but not at the lower concentration. The median anesthetic concentrations for mice, AC as determined in Example V, above, are also given in Table 2. The ratio, LFlO /AC herein referred to as the flammability margin of safety, is also given in Table 2. For purposes of comparison, similar data for flammability in oxygen which were obtained under the same conditions as for the above compounds are given for the position isomers 3-bromoand 3 chloro 1,1,1,2,2 pentafluoropropanes, which are disclosed by Burns et al., as having inhalation anesthetic properties.

TABLE 2.FLAMMABILITY OF ANESTHETICS 1 Not tested.

After thirty and sixty minutes of surgical anesthesia, the 2-bromo-1,l,1,3,3-pentafluoropropane and halothane were compared in their effects on the heart beat following intravenous administration of epinephrine in sequential 0.3 log dose increments over a range of 0.25 lg/kg. to 32 ,ug./ kg. at five minute intervals. Subsequent to the administration of epinephrine, 2-bromo-1,1,1,3,3-pentafluoropane was shown to possess anesthetic properties superior to halothane. Arrhythmias of long duration occurred frequently with halothane even at small doses of epinephrine. A dose of 4 ng. of epinephrine per kilogram of body weight consistently fibrillated dogs under halothane anesthesia. In contrast, a dose of 8 ,ug. of epinephrine per kilogram of body weight were required to induce brief arrhythmias in two of four dogs and a dose of 16 l tg./ kg. caused fibrillation in only one of four dogs under anesthesia with Z-bromo-1,1,1,3,3-pentafluoropropane.

The above property of 2-bromo-1,l,l,3,3-pentafluoropropane, whereby said compound has substantially less tendency than halothane to sensitize the heart to the action of epinephrine, indicates the usefulness of this novel anesthetic agent in cases where the surgeon desires to administer epinephrine.

The results set forth in the above table shown that the novel monohalopentafluoropropanes of this invention have substantially greater flammability margins of safety than shown by the position isomers 3-chloroand 3-bromol,1,1,2,2-pentafluoropropanes.

As will be readily apparent to those skilled in the art, other examples of the herein-defined invention can -be devised after reading the foregoing specification and claims appended hereto by various modifications and adaptations without departing from the spirit and scope of the invention. All such modifications and adaptations are included within the scope of the invention as defined in the appended claims.

What is claimed is:

1. An organic monohalopentafluoropropane having the formula CF CHXCHF in which X is selected from the group consisting of chlorine and bromine.

2. The monohalopentafluoropropane of claim 1 in which X is chlorine.

7 3. The monol1alopentafiuoropropane of claim 1 in FOREIGN PATENTS Whch X bmmme- 955,478 4/1964 Great Britain 260--653 References Cited DANIEL D. HORWITZ, Primary Examiner UNITED STATES PATENTS 5 3,362,874 1/1968 Regan 260-653 3,080,431 3/1963 Zappel et al. 260653 260-633, 456R; 424-350; 252364 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 585, 245 Dated June 15, 1971 Inventor-(s) Bernard R gan It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the specification, at col. 1, lines 48 to 51, cancel "fluoropropane is disclosed by Henne et a1. 68 J. Am. Chem. Soc'y. 446 (1946) and Arnold, U. S. Pat. 2, 558, Muray, British Pat. 908, 1 10; 3-chl0ro- 1, 1, 1, 3, 3penta703;" and insert Muray, British Pat. 908, 110; 3-ch1oro-1, 1, 1, 3, 3-pentafluoropropane is disclosed by Henne et al. 68 J. Am. Chem. Soc'y. 496 (1946) and Arnold, U. S. Pat.

2, 558, 703; at col. 1, line 53, cancel 'Reactives' and insert --Reactivities.

Signed and sealed this 28th day of December 1971.

(SEAL) Attest:

EDWARD M.F'LETCHER,JR. ROBERT GOTTSCHALK Attesting Officer Acting Commissioner of Patents FORM Po-1os0 (10-69) USCOMM DC 50375 -Pcn {I U 5, GOVERNMENT PRINYING OFFICE I989 0-356-33. 

